Title | Radical Approach to Enzymatic β-Thioether Bond Formation. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Caruso, A, Bushin, LB, Clark, KA, Martinie, RJ, Seyedsayamdost, MR |
Journal | J Am Chem Soc |
Volume | 141 |
Issue | 2 |
Pagination | 990-997 |
Date Published | 2019 01 16 |
ISSN | 1520-5126 |
Keywords | Amino Acid Sequence, Bacterial Proteins, Carbon-Sulfur Lyases, Models, Chemical, Multigene Family, Peptide Biosynthesis, Peptides, Protein Processing, Post-Translational, S-Adenosylmethionine, Streptococcus, Sulfides |
Abstract | <p>Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products that harbor diverse chemical functionalities, usually introduced via the action of a small number of tailoring enzymes. We have been interested in RiPP biosynthetic gene clusters that encode unusual metalloenzymes, as these may install as yet unknown alterations. Using a new bioinformatic search strategy, we recently identified an array of unexplored RiPP gene clusters that are quorum sensing-regulated and contain one or more uncharacterized radical S-adenosylmethionine (RaS) metalloenzymes. Herein, we investigate the reaction of one of these RaS enzymes and find that it installs an intramolecular β-thioether bond onto its substrate peptide by connecting a Cys-thiol group to the β-carbon of an upstream Asn residue. The enzyme responsible, NxxcB, accepts several amino acids in place of Asn and introduces unnatural β-thioether linkages at unactivated positions. This new transformation adds to the growing list of Nature's peptide macrocyclization strategies and expands the already impressive catalytic repertoire of the RaS enzyme superfamily.</p> |
DOI | 10.1021/jacs.8b11060 |
Alternate Journal | J Am Chem Soc |
PubMed ID | 30521328 |